Trend of extracorporeal membrane oxygenation support in patients with acute respiratory distress syndrome in South Korea

We examined and compared the clinical characteristics of acute respiratory distress syndrome (ARDS) patients who received and did not receive extracorporeal membrane oxygenation (ECMO) support. The national health insurance database of South Korea was used to obtain real-world data. All adult patients admitted to intensive care units for ARDS treatment between 1 January 2014 and 31 December 2019 were included in this study. Of the 10,173 patients with ARDS included in the analysis, 740 (7.3%) received ECMO support for a mean duration of 1.6 days (standard deviation [SD]: 2.8 days) and were assigned to the ECMO group. The ECMO group had a significantly lower mean age at 57.0 years (SD: 15.7 years) than the non-ECMO group (71.8 Â years [SD: 15.1 Â years], P < 0.001). In multivariable logistic regression, a 1-year increase in age was associated with a 5% lower prevalence of ECMO support. The annual case volume was classified into four groups by quartile ratio (Q1 [lowest], Q2, Q3, and Q4 [highest]), and Q2, Q3, and Q4 groups showed a higher prevalence of ECMO support than the Q1 group. ECMO support was also performed more frequently in high case volume centers than in low case volume centers for ARDS patients.

www.nature.com/scientificreports/ vice (NHIS) also approved the study protocol (NHIS-2021-1-424). In addition, this study was performed in accordance with the Declaration of Helsinki. The requirement for informed consent was waived by the IRB and NHIS because our study used anonymized data for analysis. We used the NHIS database for this study, which contains physical, socioeconomic, disease diagnosis, and treatment information of individuals in South Korea. As the sole public health insurance system, all disease diagnoses must be registered in the NHIS database using International Statistical Classification of Diseases and Related Health Problems-tenth revision (ICD-10) codes. Moreover, prescription information regarding any procedures and/or drugs should be registered in the NHIS database for patients to receive financial support from the government. The dates of death of the study population were also extracted and used for this study until 31 December 2020. South Koreans pay a fixed rate for health insurance premiums based on their income, with approximately 67% of their medical expenses being subsidized by the government 13 . However, those who cannot afford insurance premiums or have difficulty financially supporting themselves are included in the Medical Aid Program, which involves government support for almost all medical expenses.
Study population. All adult patients who were ≥ 18 years old and admitted to the ICU between 1 January 2014 and 31 December 2019 with a diagnosis of ARDS (J80) were included in the study. After the consensus on the Berlin Definition of ARDS in 2012 14 , ARDS was diagnosed according to respiratory failure due to acute hypoxemia, dyspnea, and increased bilateral pulmonary infiltration in South Korea. Since ARDS is a pathologic condition that can occur due to other pathologic conditions 14 , we included both cases regarding the main diagnoses and secondary diagnosis of ARDS in this study. Therefore, patients with a primary diagnosis of pneumonia and a secondary diagnosis of ARDS were included in this study. The main diagnosis was defined by the NHIS after the end of hospitalization as the disease wherein the patient's demand for treatment or examination was the greatest during their hospitalization. If a patient was admitted to the ICU twice or more with a diagnosis of ARDS, only the first episode of ICU admission was considered in this study. Among patients with ARDS in this study, patients who received ECMO support were considered as the ECMO group, while the other patients were considered as the non-ECMO group.
Study objectives. This study had three primary objectives. First, the clinical characteristics between the ECMO and non-ECMO groups were compared to examine any trend in ECMO application among patients with ARDS. Second, the overall survival times in the ECMO and non-ECMO groups were compared in patients with ARDS. Third, the factors associated with ECMO application in patients with ARDS were investigated.
Collected variables. The following variables were collected for this study: Physical variables (age and sex) were included, and the annual income level at the time of ARDS treatment was collected to reflect the socioeconomic status of patients with ARDS. The annual income level was registered in the NHIS database to determine insurance premiums, and it was classified into four groups using quartiles. The treatment results of patients with ARDS were collected and categorized into four groups namely, discharge and follow-up in the same hospital group, transfer to other long-term facility center group, discharge and outpatient clinic follow-up group, and the death within hospitalization group. The admission department was listed and classified into two groups as follows: internal medicine and non-internal medicine. Length of hospitalization (days), total cost of hospitalization (USD), and cost per day (USD) were collected. The type of hospital admission was classified into three groups (transfer from another hospital, admission through the emergency room, and admission through outpatient clinic). The annual case volume of ARDS' admission in the facility was calculated, and patients with ARDS were classified into four groups using quartiles, based on the hospital wherein they were hospitalized (Q1 ≤ 4, Q2: 5-14, Q3: 15-28, and Q4 ≥ 29). The main diagnosis of ARDS, as well as diagnoses of shock (R57) or sepsis (A40, A41, and R65.2), were collected. If patients with ARDS had a main diagnosis of sepsis, the patient was considered to have sepsis-associated ARDS. Information on the treatment of ARDS, including ECMO support, use of neuromuscular blockade (NMB), continuous renal replacement (CRRT), duration of mechanical ventilation (in days), and administration of cardiopulmonary resuscitation (CPR), were collected. To reflect the comorbid status of patients with ARDS, the Charlson comorbidity index (CCI) was calculated using the registered ICD-10 codes of underlying individual diseases (Table S1). www.nature.com/scientificreports/

Discussion
In this population-based cohort study using real-world data from South Korea, ECMO support was applied to patients with ARDS who were of younger age and had a higher annual income level. ECMO support was also performed more frequently in high case volume centers than in low case volume centers for patients with ARDS. Moreover, ECMO support was concomitant with other treatments, such as NMB use, CRRT support, and a longer duration of mechanical ventilation. Our results suggest that physical, socioeconomic, and clinicopathological conditions affect the application of ECMO support for patients with ARDS in South Korea.
In this study, the mean duration of ECMO support in patients with ARDS was 1.6 days (SD 2.8), which was relatively short compared to that observed in previous reports 15, 16 . The difference might be due to the characteristics of patients who underwent ECMO support. First, patients without extremely severe acute respiratory www.nature.com/scientificreports/ www.nature.com/scientificreports/ failure who required a longer duration of ECMO support might have been excluded, based on the indications for ECMO support, due to an expected poor treatment outcome. Table 2 supports this assumption because age and CCI were lower in the ECMO group than in the non-ECMO group. Moreover, the total cost of hospitalization was significantly higher in the ECMO group than in the non-ECMO group, suggesting that patients with ARDS who were expected to recover with a better prognosis might receive active and invasive treatments, such as ECMO support, CRRT, and CPR, in South Korea. Therefore, the results should be interpreted carefully considering the shorter duration of ECMO support in patients with ARDS in this study. The age of patients with ARDS is an important issue in the application of ECMO support. In South Korea, age is a major predictor of poorer survival outcomes in patients with ARDS who undergo ECMO support 17  www.nature.com/scientificreports/ number of elderly patients who underwent ECMO has increased in recent years, and Mendiratta et al. emphasized that old age should not be an absolute contraindication for the initiation of ECMO in patients with ARDS. Similar results were observed in the ELSO registry, and Lorusso et al. also insisted that old age should not be an absolute contraindication for applying ECMO in patients with cardiogenic shock 19 . Another study reported that hospital survival outcomes after ECMO support were similar in both elderly and young patients, suggesting that old age is not a contraindication 20 .
The results regarding annual income levels are also important in this study. We showed that patients with ARDS with lower annual income levels tended to avoid ECMO support compared to those with higher annual income levels. A previous systematic review reported that the total in-hospital cost for ECMO support ranged from 42,334 to 537,554 USD in 2013 21 . Another more recent review also reported that the costs of ECMO support ranged from USD 22,305 to USD 334,608 in 2019 22 . Although the South Korean government covers approximately two-thirds of the total medical expenses 23 , the financial burden might be a critical factor for applying ECMO support in patients with ARDS, as demonstrated in this study.
Additionally, we showed that patients with ARDS in South Korea received more ECMO support in highvolume centers than in low-volume centers. This might have been influenced by some examples concerning higher case volume centers in South Korea. First, a higher case volume center was associated with improved survival outcomes for patients with ARDS 24 . Second, a high case volume center was associated with better survival outcomes for patients who underwent ECMO support 25 . As ECMO support is a highly source-demanding www.nature.com/scientificreports/ procedure, outcome and quality of life after ECMO support might be better in selected and high-volume ECMO centers, which might affect the study results. This study has several limitations. First, the severity of ARDS was not accurately assessed. For example, the PaO 2 /FiO 2 ratio [Definition of ARDS: relation of the patient's oxygen in arterial blood (PaO 2 ) to the fraction of oxygen in the inspired air (FiO 2 )] and Acute Physiology and Chronic Health Evaluation II scores were not included in this study for the adjustment of patients with ARDS. Second, there might be missing cases of individual underlying diseases using registered ICD-10 codes, which were used to calculate the CCI. Third, an important treatment option, such as prone positioning, was not considered in this study because the prescription code of prone positioning did not exist in the NHIS database. Lastly, some important covariates, such as smoking history, pulmonary function test results, and body mass index, were not adjusted because the NHIS database did not contain these data.
In conclusion, real-world data from South Korea showed that ECMO support was applied to patients with ARDS who were of younger age and had a higher annual income level. ECMO support was also performed more frequently in high case volume centers than in low case volume centers for patients with ARDS. In addition, ECMO support was used concomitantly with other treatments such as NMB use, CRRT support, and a longer duration of mechanical ventilation. Our results suggest that physical, socioeconomic, and clinicopathological conditions affect the application of ECMO support in patients with ARDS in South Korea. Moreover, we showed that ECMO support is a highly source-demanding procedure that requires treatment in selected and high-volume ECMO centers.

Data availability
Data will be available upon reasonable request to corresponding author.